The objectives of this proposal are: 1) to establish the role, if any, of cyclic GMP in regulating cardiac function; 2) to elucidate the mechanism(s) by which cholinergic agonists modulate the effects of catecholamines on the heart; and 3) to extend the observations made in in vitro studies (in objectives 1 and 2) to experiments on the interactive roles of the sympathetic and vagal nervous systems in regulating the electrophysicological properties of the in situ dog heart. Objectives 1 and 2 will be pursued with in vitro studies, using functioning isolated tissues (perfused heart, atrial strips, Purkinje fibers) and various types of broken cell preparations. Multiple biochemical parameters, relating to autonomic receptors and the enzymes coupled to these receptors, will be assessed. Cyclic AMP and cyclic GMP levels will be measured, adenylate and guanylate cyclase activities will be assayed, and hormone interaction with beta-adrenergic receptors and muscarinic cholinergic receptors will be directly assessed with binding studies. In parallel studies, the interaction of the sympathetic and parasympathetic nervous systems in modifying the electrophysiological properties of the in situ dog heart will be examined. With this approach, it is hoped that the three objectives will be accomplished, and that information regarding mechanisms of production of lethal ventricular arrhythmias will result.